Inhibitory deficits are characteristic of the mania of Bipolar Disorder (BD) and provide a behavioral target for translational research. The primary focus of this translational project is to assess deficits in three domains of inhibition in manic BD patients and in parallel animal models based on pharmacological challenges and gene engineering technology. Extensive animal data as well as recent findings linking BD to alterations in the genetic sequence in the vicinity of the dopamine transporter (DAT) gene support the basic hypothesis that the manic state involves a dysregulation of dopaminergic systems. This project uses and further develops cross-species measures that reflect abnormalities in dopaminergic systems to advance our understanding of BD and its treatment. The design involves parallel studies in manic BD patients and in mice in which the DAT has been manipulated either pharmacologically (amphetamine) or genetically (DAT knockdown and knockout mice). Specifically, inhibitory deficits in three domains will be assessed: 1. Impaired sensorimotor inhibition using prepulse inhibition of startle; 2. Motor hyperactivity in a novel environment using species-appropriate ambulatory monitoring devices; and, 3. Perseveration using innovative non-linear analyses of spatial and temporal patterns of motor responses. Manic BD inpatients will be studied at hospital admission, when highly symptomatic, and longitudinally during treatment with antimanic and/or atypical antipsychotic drugs. Normal comparison subjects will also be studied longitudinally, although in the absence of treatment. An important innovative aspect of this application is the development of an explicit human analog of the open field, the classic rodent behavioral paradigm used to assess dopaminergic psychostimulant effects. Experiments with mice will test the hypothesis that mutant mice lacking the normal complement of DAT might serve as a model of the inhibitory deficits in BD and that DAT-deficient mice might provide an animal model with predictive validity for the identification of antimanic agents. The parallel characterization of core features of BD across species will enable objective measures of mania that can be used to monitor treatment efficacy in BD patients and facilitate the validation of homologous predictive models of BD in rodents. Such preclinical models, and the human measures essential to their validation, are critical to the future discovery of novel treatments of this condition.